The activation of cell cycle and apoptotic genes by p53 is crucial in controlling or eliminating cells that may be a threat to the whole organism. The activation of these genes must therefore be cleverly regulated since they must only be activated under exceptionalcircumstances. The goal of my proposal is to understand the mechanisms of the transcriptional response to stress by p53 and how this may play a role in influencing the cells fate. The specific aims are as follows: 1. What is the composition and function of the transcriptional machinery when assembled on cell cycle arrest and pro-apoptotic p53 target genes in response to various stresses? 2. Which p53 cofactors (including enzymes that modify p53)are required to aid in cell fate decisions in response to stress? 3. What role do the various splice variants of p63 and p73 play with regards to stress activated regulation of p53 target genes? This information will be critical for a detailed understanding of how p53 is able to mediate stress responses and will aid in the development of new therapies for various cancers.